Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU.

PURPOSE: For locally advanced primary colorectal cancer, our institution has combined intraoperative electron irradiation (IOERT) with external beam irradiation (EBRT) +/- 5-fluorouracil (5-FU) and surgical resection. Disease control and survival were compared with the current IOERT and prior non-IOERT regimens. METHODS AND MATERIALS: From April 1981 through August 1995, 61 patients received an IOERT dose of 10-20 Gy, usually combined with 45-55 Gy of fractionated EBRT; 56 had minimum follow-up of 18 months. The amount of residual disease remaining at IOERT after exploration and maximal resection in the 56 patients was gross in 16, < or = microscopic in 39, and unresected in 1. RESULTS: Survival (SR) and disease control were analyzed as a function of potential prognostic factors. Factors that achieved statistical significance for improved overall survival included treatment sequence of preop EBRT + 5-FU (vs. postoperative EBRT + 5-FU, p = 0.003) and < or = microscopic residual disease after maximal resection (vs. gross residual, p = 0.005). Those that appeared to favorably impact disease-free survival included EBRT + 5-FU (vs. EBRT alone, p = 0.01), < or = microscopic residual (vs. gross, p = 0.0014), and colon site of primary (vs. rectum, p = 0.009). Failures within an irradiation field have occurred in 4 of 16 patients (25%) who presented with gross residual after partial resection vs. 2 of 39 (5%) with < or = microscopic residual after gross total resection (p = 0.01). The significant prognostic factors for a decrease in distant metastases were the same as for disease-free SR with respective p-values of 0.013 (EBRT + 5-FU), 0.008 (microscopic residual), and 0.03 (colon primary). The current data suggests a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (< or = 12.5 Gy--1 of 29 or 3%, > or = 15 Gy--6 of 26 or 23%, p = 0.03). CONCLUSIONS: Both overall survival and disease control appear to be improved with the addition of IOERT to standard treatment. More routine use of systemic therapy is indicated as a component of IOERT containing treatment regimens because the incidence of distant metastases was 50% of patients at risk.

Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated, locally recurrent colorectal cancer.

PURPOSE/OBJECTIVE: 1) Disease control and survival will be evaluated for treatment regimens containing intraoperative electron irradiation (IOERT) for locally recurrent, previously unirradiated colorectal cancers. 2) Various prognostic factors will be evaluated to determine whether they have an impact on disease control or survival. MATERIALS AND METHODS: From April 1981 through August 1995, 123 patients with previously unirradiated locally recurrent colorectal cancers received IOERT at our institution, usually as a supplement to external beam irradiation (EBRT) and maximum resection. All received EBRT with or without concomitant 5-fluorouracil-based chemotherapy. Forty-five Gy in 25 fractions was given to the tumor or tumor bed plus 3-cm to 5-cm margins in 121 of 123 patients and a boost of 5.4 to 9 Gy in 3 to 5 fractions to the tumor plus 2-cm margins. Maximum resection was performed before or after EBRT. IOERT doses ranged from 10 to 20 Gy in 119 of 123 patients, with dose dependent on resection margins (130 fields in 123 patients). Maintenance chemotherapy was given to only two patients. RESULTS: Disease relapse and survival were evaluated. Central failure (within the IOERT field) was documented in 13 of 123 patients (11 percent) with a five-year actuarial rate of 26 percent. Local relapse (in EBRT field) occurred in 24 patients (20 percent); five-year rate was 37 percent. Distant metastases occurred in 66 patients (54 percent); five-year rate was 72 percent. Median survival was 28 months, with overall survival at two, three, and five years of 62, 39, and 20 percent, respectively. Tolerance data suggest a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (< or = 12.5 Gy, 2 of 29 or 7 percent; > or = 15 Gy, 19 of 101 or 19 percent; P = 0.12). Survival and disease control were analyzed as a function of potential prognostic factors. None of the prognostic factors had a significant impact on disease control or survival. Although there was a trend for reduction in local relapse rates with gross total vs. partial resection, this neither achieved statistical significance nor translated into improved survival. Patients with gross residual disease after maximum resection had three-year and five-year survival rates of 36 and 18 percent, respectively, which paralleled results for patients with gross total resection at 41 and 24 percent, respectively. CONCLUSION: Encouraging trends for improved local control with or without survival exist in separate locally recurrent colorectal IOERT analyses from our institution and other institutions. Therefore, continued evaluation of IOERT approaches seems warranted. Disease control within the IOERT and external fields is decreased when the surgeon is unable to accomplish a gross total resection. Therefore, it is reasonable to consistently add 5-fluorouracil or other dose modifiers during EBRT and to evaluate the use of dose modifiers in conjunction with IOERT (sensitizers and hyperthermia). In view of high systemic failure rates of > 50 percent in patients with locally recurrent disease, more routine use of systemic therapy is indicated as a component of IOERT-containing treatment regimens (use existent chemotherapy and/or develop effective immunotherapy and gene transfer therapy). Even with locally recurrent lesions, the aggressive multimodality approaches including IOERT have resulted in improved local control and long-term survival rates of 20 percent vs. an expected 5 percent with conventional techniques.

External beam plus intraoperative irradiation for gastrointestinal cancers.

Although useful palliation can often be achieved when external beam irradiation and chemotherapy are used to treat locally advanced gastrointestinal malignancies, local control and long-term survival are infrequent in view of the limited tolerance of surrounding organs and tissues. In view of dose limitations of external beam irradiation, intraoperative irradiation (IORT) with electrons has been used as a supplement to external treatment in an attempt to improve the therapeutic ratio of local control versus complications. An IORT dose of 10 to 20 Gy has been combined with fractionated external beam doses of 45 to 55 Gy in 1.8 Gy fractions in studies performed in the United States, Japan, Europe, and Scandinavian countries. In this paper the indications for and the results of aggressive combined techniques that include IORT are discussed. Results obtained with external beam techniques alone or with chemotherapy and resection are presented by site to demonstrate the need for higher doses of irradiation. When results from IORT series are compared to standard treatment with regard to disease control and survival, local control appears better with locally advanced colorectal, gastric, and pancreatic cancer; and survival appears better with colorectal +/- biliary cancers. With pancreatic cancer, improvements in local control do not translate into increased survival in view of the high incidence of subsequent liver and peritoneal failures. Implications for future strategies in all sites are discussed.

Preoperative external beam radiotherapy followed by cytoreductive surgery and intraoperative radiotherapy for locally advanced primary or recurrent renal malignancies.

Patients with local persistence or local regional recurrence of cancer after nephrectomy for renal cell cancer are unlikely to respond well to systemic therapy or external irradiation alone. In this analysis, patients with locally recurrent (9) or persistent (2) cancer following nephrectomy (renal cell cancer in 8, transitional cell or squamous cell cancer in 3) usually received 4,500 to 5,040 cGy. preoperative external beam irradiation followed by maximal surgical debulking and intraoperative electron irradiation (1,000 to 2,500 cGy.). Of 8 renal cell cancer patients 6 were alive and 4 were without disease progression at 15 to 50 months (3 of 4 at 29 months or longer). One patient died free of disease at 10.5 months and 3 had metastases (regional in 1 and distant in 3). Of the 3 transitional or squamous cell carcinoma patients 1 died free of disease 28.5 months after initiation of treatment for recurrence and 2 died of disease progression (liver in 1 and local in 1). It appears that select patients with solitary local recurrence or persistence following radical nephrectomy for renal cell cancer may benefit from an aggressive local treatment approach using irradiation (preoperatively and intraoperatively) plus maximal surgical debulking. In patients with locally advanced high grade transitional cell cancer the locally aggressive approach should probably be combined with multi-drug chemotherapy because of increased systemic risks. For both groups (renal cell carcinoma and transitional/squamous cell carcinoma) the most ideal patient for such treatment is one who has not received prior chemotherapy or external irradiation to the site of relapse, since 3 of 5 patients with disease progression after our aggressive approach had received chemotherapy (2) or external beam irradiation (2) elsewhere before referral.

External beam and intraoperative electron irradiation for locally advanced soft tissue sarcomas.

PURPOSE: Intraoperative irradiation with electrons was used in conjunction with external beam irradiation and maximal surgical resection in 20 patients with locally advanced soft tissue sarcomas or desmoids. This manuscript presents results with regard to tolerance of treatment and its impact on tumor control and survival. METHODS AND MATERIALS: Ten patients presented with previously untreated primary sarcomas and 10 at the time of local recurrence (two had recurrent desmoid tumors). Tumor location was retroperitoneal in 19 and in the low anterior neck in one. A partial or gross total resection was performed prior to the external beam or intraoperative component of irradiation in every patient, but all had positive resection margins. Patients received 4500-6000 cGy of fractionated, external beam irradiation and an IORT dose of 1000-2000 cGy. Chemotherapy was given only at the time of disease progression. RESULTS: Fourteen of 20 patients (70%) were alive; 11 (55%) were free of disease (4/10 primary, 7/10 recurrent), but 1 required hemipelvectomy for salvage. Progression within the intraoperative irradiation field was documented in only 1 patient (5%) and within the external beam field in 3/20 (15%). Blood born distant metastasis occurred in 5 patients (25%) and peritoneal seeding in 1 (5%). The distant failure incidence by grade was 1/8 (13%) for Grades 1, 2 and 5/12 (42%) for Grades 3, 4. Only 1 patient (5%) developed a > or = severe neuropathy, and small bowel obstruction requiring exploration also occurred in a single patient. CONCLUSION: In view of acceptable tolerance and the high current rate of local tumor control, in spite of incomplete surgical resections, further evaluation of intraoperative irradiation as a component of treatment is indicated for locally advanced primary and recurrent soft tissue sarcomas.

Intraoperative and external beam irradiation for locally advanced colorectal cancer.

In view of poor local control rates obtained with standard treatment, intraoperative radiation (IORT) using electrons was combined with external beam irradiation and surgical resection, with or without 5-fluorouracil (5FU), in 51 patients with locally advanced colorectal cancer (recurrent, 36 patients; primary, 15 patients). Patients received 4500-5500 cGy (rad) of fractionated, multiple field external beam irradiation and an IORT dose of 1000-2000 cGy. Thirty of 51 patients (59%) are alive and 22 patients (43%) are free of disease. In 44 patients at risk greater than or equal to 1 year, local progression within the IORT field has occurred in 1 of 44 (2%) and within the external beam field in 8 of 44 (18%). All local failures have occurred in patients with recurrence or with gross residual after partial resection, and the risk was less in patients who received 5FU during external irradiation (1 of 11, 9% vs. 6 of 31, 19%). The incidence of distant metastases is high in patients with recurrence, but subsequent peritoneal failures are infrequent. Acute and chronic tolerance have been acceptable, but peripheral nerve appears to be a dose-limiting structure. Randomized trials are needed to determine whether potential gains with IORT are real.

Intraoperative and external beam irradiation +/- 5-FU for locally advanced pancreatic cancer.

Because of the poor local control rates obtained with external beam irradiation +/- chemotherapy for locally advanced pancreatic cancer, our institution has used intraoperative radiation therapy (IORT) with electrons to deliver a single "boost" dose of radiation in 52 patients with biopsy-proven adenocarcinoma (primary, unresectable-49; primary, residual-2; and recurrent, unresectable-1). Patients received 4500-5000 rad of fractionated external beam irradiation and an IORT dose of 1750 rad (2 patients) or 2000 rad (50 patients). Acute and chronic tolerance have been acceptable. Documented local progression within either the external beam or IORT fields has been infrequent (3 of 42 evaluable patients or 7%), but there has been little, if any, change in median or long-term survival from that seen in external beam series. This is probably because of a high incidence of liver and peritoneal metastases with pancreatic cancer. A phase II pilot trial, which combines upper or total abdominal irradiation and infusion 5-FU with tumor nodal irradiation plus IORT, is in progress in our institution to evaluate tolerance and the relative incidence of abdominal failures.

Intraoperative and external beam irradiation with or without resection: Mayo pilot experience.

At our institution, intraoperative radiation therapy (IORT) with an electron beam has been administered as a single boost dose of 1,000 to 2,000 cGy (rad) in combination with 4,500 to 5,000 cGy (rad) of fractionated external beam irradiation. From April 1981 to July 1983, 50 patients received such treatment, and results are analyzed in detail in this article. All patients had locally advanced disease (initially unresectable for cure, residual after resection, or recurrent), and the main disease sites were gastrointestinal (pancreatic, colorectal, and biliary tumors) and soft tissue (sarcomas). Disease-free survival to date has been excellent in our colorectal and biliary subsets of patients. Although local progression has not been a major problem in patients with unresectable pancreatic lesions, failures in the liver and peritoneal cavity have been excessive, and treatment strategies have been altered in an attempt to decrease the frequency of such failures. Although both short-term and long-term morbidity are acceptable, pilot trials with use of radiation-dose modifiers are planned to determine whether the therapeutic ratio of local control to associated complications can be improved even further.